Our studies with the tricyclics, imipramine and nortriptyline, have tested the hypothesis they are antiarrhythmic in cardiac patients with VPDs and, moreover, have identified a new class of antiarrhythmic agents. The sustained duration of action, long half-life of elimination, lack of adverse effect on cardiac function and ejection fraction, and relatively minor adverse effects which do not limit long-term treatment are significant advantages over many marketed agents and those available for clinical trials. It is ironical that tricyclics have a potential for widespread use in cardiac patients in view of the fact they have been largely withheld from them because of effects associated with overdose. We plan studies to compare effectiveness and tolerance of this new class of agents against a standard antiarrhythmic drug; to test their efficacy in high risk patients using programmed electrophysiological stimulation; and to further characterize their pharmacokinetics and protein binding in patients with chronic stable VPDs and myocardial infarction. These studies are designed to enhance our understanding of the dynamics and kinetics of tricyclics in populations not previously exposed to them and in whom their behavior is not predictable from reports in normal volunteers and depressed patients. The long term goal is to improve our rational use of an outstanding new class of antiarrhythmic drugs for chronic oral therapy in cardiac patients.